Dominique Genre

Cost–effectiveness of repeated aphereses in poor mobilizers undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation

Cost–effectiveness of repeated aphereses in poor mobilizers undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation

High-dose sequential chemotherapy with stem cell support for non-metastatic breast cancer

The importance of dose-intensity has been suggested in breast cancer. The aim of this study was to evaluate the feasability of a high-dose intensity doxorubicin-cyclophosphamide regimen with supporting G-CSF and blood stem cells. Twenty-five patients with non-metastatic breast cancer received four cycles of doxorubicin (75 mg/m2) and cyclophosphamide (3000 mg/m2) at 3 week intervals. Apheresis was performed after the first cycle and if necessary after the second cycle. Stem cells were reinfused after the third and fourth cycles. G-CSF was started on day 3 of each cycle (5 μ g/kg/day) and was stopped the day before the last apheresis or when absolute neutrophil count was above 0.5 × 109/l. Median received dose-intensity was respectively 25 mg/m2/week (range 22–26) and 1000 mg/m2/week (range 904–1065) for doxorubicin and cyclophosphamide. Grade IV thrombocytopenia occurred in 8% of cycles. Two patients needed platelets and 12 red cell transfusion. Fifteen patients were readmitted for a median duration of 4 days (range 1–7). We have established a safe, outpatient, high-dose intensity doxorubicin-cyclophosphamide regimen with supporting G-CSF and blood stem cells which can be submitted for comparison with the current standards.

Participants' uptake of clinical trial results: a randomised experiment.

Background:Participants are showing great interest these days in obtaining the results of clinical trials. The aim of this study was to assess patients’ uptake and understanding of the results of the trial in which they have participated and the impact of a letter offering patients the possibility of consulting the trial results on a specific website.Methods:Breast cancer patients participating in a trial on the efficacy of Trastuzumab were randomly subdivided into an Internet group (who received the letter of invitation) and a control group (who did not receive it). Among 115 HER2-positive women from 21 centres, 107 (93%) answered a self-administered questionnaire.Results:Most of the patients in both groups had access to the Internet (72.0%). The majority (97.2%) stated that receiving information about the trial results would be useful, and the oncologist was the most frequently preferred information provider. The Internet groups declared uptake of the trial results was only slightly higher (47.1% vs 33.9%; P=0.166); however, they understood the results significantly more accurately (18.8% vs 5.6%; P=0.039).Interpretation:Although Internet was not the respondents’ preferred source of information, the possibility of using this source slightly increased the uptake and understanding of the results.

Occult tumor cell contamination in patients with stage II/III breast cancer receiving sequential high-dose chemotherapy

Summary:The purpose of this study was to evaluate the presence of micrometastatic cells in the apheresis products from patients with breast cancer, and also to determine if repeated infusion of contaminated products had any clinical impact. A total of 94 patients with high-risk breast cancer were enrolled in a prospective single center study to evaluate the use of dose-intensified chemotherapy (doxorubicine 75 mg/m2 and cyclophosphamide 3000 or 6000 mg/m2 for four cycles) with repeated (× 2) stem cell reinfusion. All women were monitored for the presence of metastatic cells in aphereses, collected after first course of intensive chemotherapy, and following additional mobilization with rhG-CSF. Epithelial cells were screened with monoclonal antibodies directed to cytokeratin. Eight of the 94 patients had detectable tumor cells in one or several aphereses collected after intensive chemotherapy; this was unrelated to other tumor characteristics, including size, histology, Scarff Bloom and Richardson (SBR) grading (presence or absence of hormone receptors). Hemato-poietic reconstitution was similar in the cells from these eight patients, and in the total patient population. Three of these eight patients relapsed. This study has confirmed that contamination of apheresis products remains a rare event, which does not seem to affect clinical evolution, even when reinfused into the patient.

Transient detection of β-galactosidase activity in hematopoietic cells, following reinjection of retrovirally marked autologous blood progenitors in patients with breast or ovarian cancer receiving high-dose chemotherapy

Abstract Objective The aim of this report is to demonstrate the feasibility and safety of genetically modifying autologous human blood CD34 + cells in vitro, with a retroviral vector that encodes a marker gene. The fate of genetically modified cells and their progeny was followed in vivo, after reinfusion in patients treated with high-dose chemotherapy for poor-prognosis breast or ovarian carcinomas. Patients and Methods Six patients received genetically modified autologous peripheral blood progenitors, together with unmanipulated aphereses, following high-dose chemotherapy. CD34 + cells were immunoselected from aphereses, and retrovirally transduced by coculture with the retroviral vector producing cell line, to express a nuclear localized version of E. coli β-galactosidase, encoded by a defective Moloney-murine leukemia virus–derived retroviral vector. Cells were reinfused to the patients after myeloablation, without prior ex vivo selection. Results Five out of six patients showed the transient presence of low numbers of β-galactosidase + cells, as detected with an immunocytochemical assay, in the peripheral blood, during the first month following infusion. One patient had β-galactosidase + clonogenic progenitors in her marrow at two months after transplantation, including HPP-CFC; intriguingly, this patient had the lowest percentage of X-gal + cells in her graft. Patients experienced side effects that are often observed after high-dose chemotherapy. Conclusions Feasibility and safety of genetic modification of human hematopoietic stem and progenitor cells are demonstrated by this study. Ex vivo or in vivo selection is not mandatory, even in clinical situations where transduced cells have no survival advantage over wild-type cells; however, significant improvements in gene transfer technology are needed to achieve potentially useful levels of expression in such clinical situations.

Modulations of dose intensity of doxorubicin and cyclophosphamide in association with G-CSF and peripheral blood stem cells in adjuvant chemotherapy for breast cancer: comparative evaluation of completion and safety of three intensive regimens

The aim of this study was to evaluate and to compare in terms of toxicity the modulations of dose intensity of cyclophosphamide and doxorubicin in adjuvant chemotherapy for high-risk breast cancer. Four cycles of sequential high-dose chemotherapy with doxorubicin and cyclophosphamide (AC), supported with G-CSF and peripheral blood stem cells (PBSC) were administered to 81 women. Three successive cohorts were studied: doxorubicin (75 mg/m2) + cyclophosphamide (3000 mg/m2) every 21 days (group 1), doxorubicin (75 mg/m2) + cyclophosphamide (3000 mg/m2) every 15 days (group 2), and doxorubicin (75 mg/m2) + cyclophosphamide (6000 mg/m2) every 21 days (group 3). Seventy-five patients received four cycles of treatment with a total of 310 cycles administered. The received dose intensity of doxorubicin was higher in group 2 and that of cyclophosphamide was lower in group 1 than in the other two groups. Hematological and extra-hematological toxicities, as well as the number and duration of hospitalizations for toxicity, were significantly higher in group 3. We conclude that the group 3 regimen is associated with toxicities comparable to autologous transplantation. Increasing dose intensity of doxorubicin and cyclophosphamide is feasible in an outpatient setting and safe in groups 1 and 2 with the support of hematopoietic factor and PBSC.

Intensive sequential dose dense chemotherapy with stem cell support as first-line treatment in advanced ovarian carcinoma: a phase II study.

From August 1995 to December 1997, 15 patients with stage III–IV ovarian cancer were treated with outpatient intensive chemotherapy with G-CSF and stem cell support. The first cycle consisted of cyclophophamide IV 6 g/m2; second, third, fourth and fifth paclitaxel 250 mg/m2 and the sixth and seventh carboplatin AUC 18. CD34+ cells were collected after the first cycle and reinfused after completion of cycles 6 and 7. Fourteen patients had stage IIIc and one patient had stage IV disease with liver metastases. All patients underwent laparotomy to maximize tumor debulking. This was optimal in eight patients and suboptimal in seven patients. Second-look surgery was performed in 14 patients. All patients had macroscopic complete responses and 10 patients had complete histologic response. Median follow-up was 48 months (range, 20 to 62). Twelve patients had further progression at a median of 27 months (range, 9 to 42) and nine are alive, three without evidence of disease progression. This pilot study shows that dose-dense chemotherapy with paclitaxel and carboplatin is associated with low toxicity and may improve the outcome of patients with poor prognosis ovarian cancer.

Marketing Authorization Procedures for Advanced Cancer Drugs.

Background. The past decades have seen advances in cancer treatments in terms of toxicity and side effects but progress in the treatment of advanced cancer has been modest. New drugs have emerged improving progression free survival but with little impact on overall survival, raising questions about the criteria on which to base decisions to grant marketing authorizations and about the authorization procedure itself. For decisions to be fair, transparent and accountable, it is necessary to consider the views of those with relevant expertise and experience. Methods. We conducted a Q-study to explore the views of a range of stakeholders in France, involving: 54 patients (18 months after diagnosis); 50 members of the general population; 27 oncologists; 19 healthcare decision makers; and 2 individuals from the pharmaceutical industry. Results. Three viewpoints emerged, focussing on different dimensions entitled: 1) ‘Quality of life (QoL), opportunity cost and participative democracy’; 2)‘QoL and patient-centeredness’; and 3) ‘Length of life’. Respondents from all groups were associated with each viewpoint, except for healthcare decision makers, who were only associated with the first one. Conclusion. Our results highlight plurality in the views of stakeholders, emphasize the need for transparency in decision making processes, and illustrate the importance of a re-evaluation of treatments for all 3 viewpoints. In the context of advanced cancer, our results suggest that QoL should be more prominent amongst authorization criteria, as it is a concern for 2 of the 3 viewpoints.

Transparency in the presentation of trial results may not increase patients' trust in medical researchers.

Background One of the expected benefits of sharing trial results with participants is that it may enhance trust in medical researchers (TMRs). Purpose In a prospective study on a sample of clinical trial participants, we investigated the effect on the participants’ TMRs of providing final trial results to participants via the Internet. Methods Participants in the FNCLCC-PACS04 trial (ClinicalTrials.gov Identifier: NCT00054587) were surveyed on average 6 years after enrollment, when the trial results were available. In the current study, they were randomized to receive (experimental group) or not to receive (control group) a letter informing them that the results of the trial could be consulted on a specific website. TMRs was measured before randomization and 6 months later using mailed self-administered questionnaires. Results The response rate was 93% (N = 107). TMRs remained unchanged in the control group (mean effect size = −0.06, 95% confidence interval (CI): −0.28 to 0.17, p = 0.617) but decreased in the experimental group (−0.30, 95% CI: −0.53 to −0.06, p = 0.015). However, the difference between the two effect sizes was not statistically significant (p = 0.144). Limitations The results obtained here on the disclosure of final trial results to breast cancer patients via the Internet cannot be generalized to all situations involving the disclosure of phase III randomized controlled trial results. Conclusions Transparency is an ethical research requirement, but it may not enhance participants’ TMRs.

Décision de participer à un essai clinique en cancérologie: influence du vécu sur les attitudes

RésuméL’objectif de cette étude était de comparer les attitudes théoriques par rapport à la participation ou non à un essai randomisé contrôlé (ERC) de trois groupes comparables de patientes suivies prospectivement (cancer du sein non métastatique traité par chimiothérapie standard): ayant eu une proposition de participer à un ERC (201 acceptations, 66 refus) ou pas (n = 188). Le refus de participer semble être une décision personnelle, alors que le souhait reflète davantage l’approbation de la proposition du médecin. Lors de la proposition de participation, les médecins doivent faire face à une aversion envers le procédé de randomisation et discuter abondamment des raisons et de l’importance de la randomisation ainsi que de tous les aspects de la participation à un ERC afin de transmettre aux patients toute l’information nécessaire pour prendre une décision informée.AbstractThe aim of this study was to compare, theoretically, attitudes towards participating or declining to participate in a hypothetical randomized controlled trial (RCT) involving three comparable breast cancer patient groups surveyed prospectively (non-metastatic cancer treated with standard chemotherapy): some patients were invited to participate in the clinical RCT (201 acceptances, 66 refusals) and others were not (n = 188). Patients’ acceptance to participate reflected their physicians’ approval, whereas refusal was usually a personal choice. When proposing RCTs, physicians must address patients’ negative preconceptions about randomization. Physicians should thoroughly discuss the reasons for and importance of randomization as well as the other aspects of participating in clinical trials in order to provide patients with all the information they need to make informed decisions.